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PBT-6, a Novel PI3KC2γ Inhibitor in Rheumatoid Arthritis

Biomolecules & Therapeutics 2020년 28권 2호 p.172 ~ 183
 ( Kim Ju-Young ) - Inha University College of Medicine Department of Medicine

정경희 ( Jung Kyung-Hee ) - Inha University College of Medicine Department of Medicine
 ( Yoo Jae-Ho ) - Sungkyunkwan University School of Pharmacy
박정희 ( Park Jung-Hee ) - Inha University College of Medicine Department of Medicine
 ( Yan Hong Hua ) - Inha University College of Medicine Department of Medicine
 ( Fang Zhenghuan ) - Inha University College of Medicine Department of Medicine
임주한 ( Lim Joo-Han ) - Inha University College of Medicine Department of Medicine
권성렬 ( Kwon Seong-Ryul ) - Inha University College of Medicine Department of Medicine
김명구 ( Kim Myung-Ku ) - Inha University College of Medicine Department of Medicine
박현주 ( Park Hyun-Ju ) - Sungkyunkwan University School of Pharmacy
홍순선 ( Hong Soon-Sun ) - Inha University College of Medicine Department of Medicine

Abstract


Phosphoinositide 3-kinase (PI3K) is considered as a promising therapeutic target for rheumatoid arthritis (RA) because of its involvement in inflammatory processes. However, limited studies have reported the involvement of PI3KC2γ in RA, and the underlying mechanism remains largely unknown. Therefore, we investigated the role of PI3KC2γ as a novel therapeutic target for RA and the effect of its selective inhibitor, PBT-6. In this study, we observed that PI3KC2γ was markedly increased in the synovial fluid and tissue as well as the PBMCs of patients with RA. PBT-6, a novel PI3KC2γ inhibitor, decreased the cell growth of TNF-mediated synovial fibroblasts and LPS-mediated macrophages. Furthermore, PBT-6 inhibited the PI3KC2γ expression and PI3K/ AKT signaling pathway in both synovial fibroblasts and macrophages. In addition, PBT-6 suppressed macrophage migration via CCL2 and osteoclastogenesis. In CIA mice, it significantly inhibited the progression and development of RA by decreasing arthritis scores and paw swelling. Three-dimensional micro-computed tomography confirmed that PBT-6 enhanced the joint structures in CIA mice. Taken together, our findings suggest that PI3KC2γ is a therapeutic target for RA, and PBT-6 could be developed as a novel PI3KC2γ inhibitor to target inflammatory diseases including RA.

키워드

Rheumatoid arthritis; Collagen-induced arthritis; PI3KC2γ; RANKL
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